Overview of Grafts for Bone Repair
Implantable materials are used in a variety of applications, often to repair or replace tissue. Implantable materials are of particular interest in the repair of bone defects. The rapid and effective repair of bone defects caused by injury, disease, wounds, or surgery has long been a goal of orthopedic surgery. Toward this end, a number of compositions and implantable materials have been used or proposed for use in the repair of bone defects. The biological, physical, and mechanical properties of the compositions and materials are among the major factors influencing their suitability and performance in various orthopedic applications.
Autologous cancellous bone (“ACB”) long has been considered the gold standard for bone grafts. ACB includes osteogenic cells, which have the potential to assist in bone healing, is nonimmunogenic, and has structural and functional characteristics that should be appropriate for a healthy recipient. Some people do not have adequate amounts of ACB for harvesting. These people include, for example, older people and people who have had previous surgeries. Further, there is reluctance to harvest ACB because of pain at the harvest site and donor morbidity.
Much effort has been invested in the identification and development of alternative bone graft materials. Urist has published seminal articles on the theory of bone induction and a method for decalcifying bone, i.e., making demineralized bone matrix (DBM). Urist M. R., Bone Formation by Autoinduction, Science 1965; 150(698):893-9; Urist M. R. et al., The Bone Induction Principle, Clin. Orthop. Rel. Res. 53:243-283, 1967. DBM is an osteoinductive material, in that it induces bone growth when implanted in an ectopic site of a rodent, owing to the osteoinductive factors contained within the DBM. Honsawek et al. (2000). There are numerous osteoinductive factors, e.g., BMP 1-18, which are part of the transforming growth factor-beta (TGF-beta) superfamily. BMP-2 has been widely studied. There are also other proteins present in DBM that are not osteoinductive alone but still contribute to bone growth, including fibroblast growth factor-2 (FGF-2), insulin-like growth factor-I and -II (IGF-I and IGF-II), platelet derived growth factor (PDGF), and transforming growth factor-beta 1 (TGF-beta.1). (Hauschka, et al. 1986; Canalis, et al, 1988; Mohan et al. 1996.)
Various cocktails of growth factors have been measured in DBM, including BMP2, TGFβ1, FGFa, IGF-I, PDGF, VEGF (Wildemann et al, 2007), BMP4 (Blum et al, 2004 and Honsaweket et al, 2005), and BMP7 (Pietrzak et al, 2006). Other extracellular matrix proteins have also been measured, including type I collagen, fibronection, Bone Sialoprotein (BSP), and osteopontin (Shigeyama et al, 1995). Combinations of growth factors may be more osteoinductive than a single growth factor (Kawai et al, 2006, Mehlhorn et al, 2007, Shintani et al, 2007, Raiche et al, 2004 and Ripamonti et al, 1997). DBM extracellular matrix proteins such as collagen may be used as carriers for the growth factors (Reddi et al, 2000).
DBM implants have been reported to be particularly useful (see, for example, U.S. Pat. Nos. 4,394,370, 4,440,750, 4,485,097, 4,678,470, and 4,743,259; Mulliken et al., Calcif Tissue Int 33:71, 1981; Neigel et al., Opthal. Plast. Reconstr. Surg. 12:108, 1996; Whiteman et al., J. Hand. Surg. 18B:487, 1993; Xiaobo et al., Clin. Orthop. 293:360, 1993, each of which is incorporated herein by reference). Useful DBM implants are disclosed in U.S. Pat. Nos. 5,073,373; 5,284,655; 5,290,558; 5,314,476; 5,507,813; 5,510,396; and 5,676,146, each of which is incorporated by reference herein.
DBM may be derived from donated human tissue. The bone is removed aseptically and treated to kill any infectious agents. The bone is typically particulated by milling or grinding, and then the mineral component is extracted by various methods, such as by soaking the bone in an acidic solution. The remaining matrix is malleable and can be further processed and/or formed and shaped for implantation into a particular site in the recipient.
In some grafts, non-bone materials may be used, including hydroxyapatite, ceramics, calcium sulfate, calcium phosphates, tricalcium phosphate, bioactive glasses, other materials, and combinations of these.
In some applications, the graft material (which also may be referred to as a delivered material), which may include biologics and/or non-bone materials, are combined with a carrier. The delivered material-carrier combination then may be shaped into a suitable bone graft.
Carriers
Generally, a carrier may be employed to facilitate in vivo use and/or formation of a particular configuration of the implantable material. In considering carriers for combination with a delivered material, it is desirable to have a carrier that has minimal effect on bioactive compounds and/or biocompatible compounds of the delivered material. Suitable carriers may include, for example, glycerol or hydrogel. The specific carrier used may be selected based on desired handling characteristics and surgeon preference.
Hydrogels exhibit many properties that make them suitable carriers for implantable materials used in the repair of bone and other tissue defects. For example, hydrogels exhibit controlled viscosity over a wide range of values, strong resistance to surgical irrigation, and excellent biocompatibility. Hydrogels are formed of a highly absorbent natural or synthetic polymer base material dispersed in water. Water has been the universal solvent for hydrogels because those skilled in the art have not perceived disadvantages to the use of water, and because nonaqueous solvents for hydrogels have been thought impractical or impossible.
The inventors have determined that, while hydrogels may provide suitable or desirable handling characteristics to an implantable material, the presence of water may have deleterious effects on the bioactivity of the material, and/or on the material's shelf life. Accordingly, a process that adequately solubilizes or otherwise disperses the polymeric base material of a hydrogel in a nonaqueous solvent, or a water substitute, but which produces a material having similar or superior physical and biologic properties to hydrogels as a carrier, is desirable. The have developed, and disclose herein, a method for preparing a hydrogel carrier that has a substantial absence of water.